Macrophage migration inhibitory factor rescues mesenchymal stem cells from doxorubicin-induced senescence though the PI3K-Akt signaling pathway

Doxorubicin (DOXO), an anthracycline antibiotic, is a commonly used anticancer drug. Despite its widespread usage, the therapeutic effects of DOXO are limited by its cardiotoxicity. Mesenchymal stem cell (MSC)-based therapies have had positive outcomes in the treatment of DOXO-induced cardiac damage; however, DOXO exerts toxic effects on MSCs, decreasing the effectiveness of MSC therapy. Macrophage migration inhibitory factor (MIF) promotes MSC survival and rejuvenation, and thus is a promising candidate to protect MSCs against DOXO-induced injury. The present study revealed that DOXO induced the senescence of MSCs, resulting in decreased proliferation, viability and paracrine effects. However, pretreatment with MIF improved the proliferation rate, viability, paracrine function, telomere length and telomerase activity of MSCs. Furthermore, the results indicated that the molecular mechanism underlying the anti-senescent function of MIF involved the phosphatidylinositol 3-kinase (PI3K)-RAC-alpha serine/threonine-protein kinase (Akt) signaling pathway, which MIF activated. In agreement with this finding, silencing Akt was identified to abolish the anti-senescent effect of MIF. In addition, MIF decreased oxidative stress in MSCs, as revealed by the decreased production of reactive oxygen species and malondialdehyde, and the increased activity of superoxide dismutase. These results indicate that MIF can rescue MSCs from a state of DOXO-induced senescence by inhibiting oxidative stress and activating the PI3K-Akt signaling pathway. Thus, treatment with MIF may have an important therapeutic application for the rejuvenation of MSCs in patients with cancer being treated with DOXO.